Lipid hydroperoxide-mediated DNA damage
Lipid hydroperoxide-mediated DNA damage
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DOI：
10.1016/s0531-5565(01)00133-4
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发表时间：
2001-09-01
影响因子：
3.9
通讯作者：
Blair, IA
中科院分区：
文献类型：
--
作者：
Blair, IA
脂质过氧化氢是在体内通过活性氧对多不饱和脂肪酸的作用而形成的自由基途径。它们也作为脂氧合酶和环加氧酶的特异性产物形成。均裂：脂质氢过氧化物分解为α，β-不饱和醛基因毒素、4-氧代-2-壬烯醛、4，5-环氧-2（E）-癸烯醛和4-羟基-2-壬烯醛通过两种完全不同的途径发生。一种途径涉及衍生自脂质过氧化氢的烷氧基的复杂重排，另一种途径涉及另一种潜在遗传毒素4-氢过氧基-2-壬烯醛的中间体形成。4，5-环氧-2（E）-癸烯醛与DNA形成未取代的乙烯基-2-脱氧腺苷加合物，这是一种在人体组织DNA样本中观察到的致突变损伤。从4-氧代-2-壬烯醛与DNA的反应中鉴定出几种新的乙醇和乙烯基DNA加合物。4-羟基-2-壬烯醛与2 '-脱氧鸟苷形成丙加合物。它还可以上调环氧合酶-2的表达。由于环氧合酶-2将亚油酸转化为脂质氢过氧化物，这为增加基因毒性双功能亲电体的产生提供了潜在的机制。丙二醛（β-羟基-丙烯醛）是另一种遗传毒性双功能亲电体，在含有两个以上双键的脂质氢过氧化物的均裂分解过程中形成。丙二醛的其他来源包括，羟基自由基介导的2 '-脱氧核糖DNA骨架的分解和血栓烷A生物合成过程中作为副产物的形成（2）。丙二醛与DNA反应，主要与2 '-脱氧鸟苷（M（1）G-dR）形成丙加合物。在过去的十年中，脂质过氧化氢衍生的内源性DNA加合物的表征和分析取得了重大进展，使人群的剂量学研究成为可能。这些研究将有助于阐明脂质过氧化氢衍生的内源性DNA作为癌症、心血管疾病和神经退行性疾病（三种最常见的衰老疾病）介质的作用。(C)2001 Elsevier Science Inc. All rights reserved.
Lipid hydroperoxides are formed in vivo through free radical pathways from the action of reactive oxygen species on polyunsaturated fatty acids. They are also formed as specific products of lipoxygenases and cyclooxygenases. Homolytic: decomposition of lipid hydroperoxides to the alpha,beta -unsaturated aldehyde genotoxins, 4-oxo-2-nonenal, 4,5-epoxy-2(E)-decenal, and 4-hydroxy-2-nonenal occurs through two quite distinct pathways. One pathway involves a complex rearrangement of the alkoxy radical derived from the lipid hydroperoxide and the other pathway involves the intermediate formation of another potential genotoxin, 4-hydroperoxy-2-nonenal. 4,5-Epoxy-2(E)-decenal forms the unsubstituted etheno-2-deoxyadenosine adduct with DNA, a mutagenic lesion which has been observed in human tissue DNA samples. Several new ethano- and etheno-DNAadducts have been identified from the reaction of 4-oxo-2-nonenal with DNA. 4-Hydroxy-2-nonenal forms propano adducts with 2'-deoxyguanosine. It can also up-regulate cyclooxygenase-2 expression. As cyclooxygenase-2 converts linoleic acid into lipid hydroperoxides, this provides a potential mechanism for increased production of genotoxic bifunctional electrophiles. Malondialdehyde (beta -hydroxy-acrolein), another genotoxic bifunctional electrophile, is formed during homolytic decomposition of lipid hydroperoxides that contain more than two double bonds. Other sources of malondialdehyde include, hydroxyl radical-mediated decomposition of the 2'-deoxyribose DNA backbone and formation as a side-product during the biosynthesis of thromboxane A(2). Malondialdehyde reacts with DNA to form primarily a propano adduct with 2'-deoxyguanosine (M(1)G-dR). Significant advances in the characterization and analysis of lipid hydroperoxide-derived endogenous DNA-adducts have been made over the last decade so that dosimetry studies of human populations are now possible. Such studies will help elucidate the role of lipid hydroperoxide-derived endogenous DNA as mediators of cancer, cardiovascular disease, and neurodegeneration, the three most prevalent diseases of aging. (C) 2001 Elsevier Science Inc. All rights reserved.